In recent years, with the early diagnosis and finding of cancer made possible through periodic medical examination, successful removal rate of the primary cancer by surgical operations has improved steadily. However, the multidrug chemotherapy or the combined therapy of chemotherapy and radiotherapy is still used for the treatment of late-stage cancer or the cancer accompanied by a metastatic focus.
Particularly, since the early diagnosis of malignant tumors with high-grade malignancy such as melanoma, lung cancer, liver cancer and pancreatic cancer is difficult, by the time the malignant tumor is diagnosed, the primary tumor, and metastatic tumor can already exist simultaneously, and surgical operations are impossible in many cases. In those cases, the combined chemotherapy with multi-anticancer drugs is widely used in treatment of such malignant tumors.
At present, cytotoxic anticancer drugs such as alkylating drugs, antimetabolites, anticancer antibiotics, plant alkaloids, platinum-based drugs are known for being the anticancer drugs widely used in clinic. However, cytotoxic anticancer drugs cause damage not only on cancer cells, but also on normal cells with active cytokinesis as well. Due to side effects caused by the cytotoxic anticancer drugs such as bone marrow suppression, cardiotoxicity, hematopoietic disorders, digestive disturbances, alopecia and the like, the effective quantity of the drug needed for cancer therapy cannot be administered, which is the fatal flaw of cytotoxic anticancer drugs.
Cyclophosphamide, an alkylating drug, is widely used in clinic, because of its effectiveness on acute leukemia, malignant lymphoma, multiple myeloma and the like. Cyclophosphamide is a drug that blocks cell proliferation by alkylating DNA, and thus suppressing DNA function. Since this drug blocks not only the proliferation of cancer cells but even the proliferation of normal cells, the side effects can occur. Vomiting, diarrhea, alopecia, bone marrow suppression and the like, are known to be the side effect.
Adriamycin (doxorubicin), an anticancer antibiotic, is widely used in clinic, and is effective in various kinds of cancers which include blood cancers such as acute leukemia and malignant lymphoma, and solid tumors such as lung cancer, breast cancer and osteosarcoma. However, it is known that adriamycin will cause side effects such as bone marrow suppression, cardiotoxicity, stomatitis, digestive disturbances and alopecia. In particular, the cardiotoxicity caused by adriamycin is a serious side effect which poses a clinical problem and causes the doses to be restricted. (William Lown J et al.: Strand scission of DNA by bound adriamycin and daunorubicin in the presence of reducing agents. Biochem. Biophys. Res. Commun., 76(3):705-710, 1977).
Cisplatin, a platinum-based drug, is a broad-spectrum anticancer drug. However, the clinical doses are to be restricted, because of the side effects such as digestive disturbances (mainly including nausea or vomiting), general malaise, kidney failure and hematopoietic disorders. Moreover, in order to reduce these side effects, a cisplatin derivative known as carboplatin was synthesized. Even though the side effects caused by carboplatin are lower than the side effects caused by cisplatin, the problem of carboplatin is the weak anticancer activity.
Under such conditions, the development of drug that reduces the side effects of anticancer drugs is strongly requested for clinical use. Until now, one agent was reported for reducing side effects of an anticancer drug. Such agent is characterized by comprising a nitrotriazole-derivative for reducing side effects of a cytotoxic anticancer drug (Japanese Patent No. 3482418). This reference has reported that a nitrotriazole-derivative suppresses the loss of body weight, which is the side effect of many anticancer drugs.
Moreover a pterin-derivative or neopterin derivative is reported as the active constituent of a cancer metastasis inhibitor and the side effect treating agent for anticancer drugs (Japanese Patent No. 3156112). This reference explains that the pterin and neopterin derivatives can suppress cancer metastasis, which leads to survival benefits; and reduces the side effects of anthraquinone anticancer drugs such as cardiotoxicity.
The thrombin-like enzyme, batroxobin which is derived from the venom of Bothrops atrox moojeni, was reported to be effective in the suppression of metastasis and proliferation of malignant tumors (Chmielewska J et al.: Effect of defibrination with batroxobin on growth and metastasis of JW sarcoma in mice. Europ. J. Cancer, 16:919-923, 1980). The technologies disclosed in this reference are based on the assumption that fibrinogen functions as a barrier to protect malignant tumor cells from the attacks of the immune system. In the technologies, a thrombin-like enzyme reduces fibrinogen levels, thus making it easier for the immune system to attack the malignant tumor cells, resulting batroxobin blocks the proliferation and metastasis of tumor cells. But, reported examples on the connection of batroxobin and reduction of the side effects of anticancer drugs do not exist.